Evidence for tmTNF reverse signaling in vivo: Implications for an Arginase-1 mediated therapeutic effect of TNF-inhibitors during inflammation.

There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2−) production than young. Acute inhibition of both NOS, with NG-nitro-l-arginine methyl ester, and arginase, with 2( S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O2− production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O2− production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

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Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2011.10.487 ◽

2012 ◽

Vol 52 (2) ◽

pp. 377-391 ◽

Cited By ~ 115

Author(s):

Chien-Ju Lin ◽

Chin-Cheng Lee ◽

Yung-Luen Shih ◽

Tsung-Yao Lin ◽

Sheng-Hao Wang ◽

...

Keyword(s):

Malignant Glioma ◽

Therapeutic Effect

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Kartogenin enhances the therapeutic effect of bone marrow mesenchymal stem cells derived exosomes in cartilage repair

Nanomedicine ◽

10.2217/nnm-2019-0208 ◽

2020 ◽

Vol 15 (3) ◽

pp. 273-288 ◽

Cited By ~ 1

Author(s):

Chun Liu ◽

Yun Li ◽

Zhijian Yang ◽

Zhiyou Zhou ◽

Zhihao Lou ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Therapeutic Effect ◽

Bone Marrow Mscs ◽

In Vivo Experiments ◽

Marrow Mesenchymal Stem Cells ◽

Cartilage Diseases

The effectiveness of mesenchymal stem cells (MSC) in the treatment of cartilage diseases has been demonstrated to be attributed to the paracrine mechanisms, especially the mediation of exosomes. But the exosomes derived from unsynchronized MSCs may be nonhomogeneous and the therapeutic effect varies between samples. Aim: To produce homogeneous and more effective exosomes for the regeneration of cartilage. Materials & methods: In this study we produced specific exosomes from bone marrow MSCs (BMSC) through kartogenin (KGN) preconditioning and investigated their performance in either in vitro or in vivo experiments. Results & conclusion: The exosomes derived from KGN-preconditioned BMSCs (KGN-BMSC-Exos) performed more effectively than the exosomes derived from BMSCs (BMSC-Exos). KGN preconditioning endowed BMSC-Exos with stronger chondral matrix formation and less degradation.

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Differential Regulation of L-Arginine Metabolism through Arginase 1 during Infection with Leishmania mexicana Isolates Obtained from Patients with Localized and Diffuse Cutaneous Leishmaniasis

Infection and Immunity ◽

10.1128/iai.00963-19 ◽

2020 ◽

Vol 88 (7) ◽

Author(s):

Arturo A. Wilkins-Rodríguez ◽

Armando Pérez-Torres ◽

Alma R. Escalona-Montaño ◽

Laila Gutiérrez-Kobeh

Keyword(s):

Cutaneous Leishmaniasis ◽

Clinical Manifestations ◽

Differential Regulation ◽

Leishmania Mexicana ◽

Arginine Metabolism ◽

Content Type ◽

Arginase 1 ◽

Oxide Synthase ◽

Inducible Nitric Oxide

ABSTRACT l-Arginine metabolism through arginase 1 (Arg-1) and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of leishmaniasis. Infection with Leishmania mexicana can cause two distinct clinical manifestations: localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). In this work, we analyzed in an in vivo model the capacity of two L. mexicana isolates, one obtained from a patient with LCL and the other from a patient with DCL, to regulate the metabolism of l-arginine through Arg-1 and NOS2. Susceptible BALB/c mice were infected with L. mexicana isolates from both clinical manifestations, and the evolution of the infection as well as protein presence and activity of Arg-1 and NOS2 were evaluated. The lesions of mice infected with the DCL isolate were bigger, had higher parasite loads, and showed greater protein presence and enzymatic activity of Arg-1 than the lesions of mice infected with the LCL isolate. In contrast, NOS2 protein synthesis was poorly or not induced in the lesions of mice infected with the LCL or DCL isolate. The immunochemistry analysis of the lesions allowed the identification of highly parasitized macrophages positive for Arg-1, while no staining for NOS2 was found. In addition, we observed in lesions of patients with DCL macrophages with higher parasite loads and stronger Arg-1 staining than those in lesions of patients with LCL. Our results suggest that L. mexicana isolates obtained from patients with LCL or DCL exhibit different virulence or pathogenicity degrees and differentially regulate l-arginine metabolism through Arg-1.

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IMMU-10. ESTABLISHING EFFECTIVE MODELS FOR IMMUNOTHERAPY IN GBM

Neuro-Oncology ◽

10.1093/neuonc/noz175.504 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi121-vi121

Author(s):

Daniel Zamler ◽

Er-Yen Yen ◽

Takashi Shingu ◽

Jiangong Ren ◽

Cynthia Kassab ◽

...

Keyword(s):

Mouse Model ◽

Cell Function ◽

Genetically Engineered ◽

Death Sentence ◽

Immune Microenvironment ◽

Knockout Mouse Model ◽

Arginase 1 ◽

Genetically Engineered Mouse Model ◽

Human Gbm

Abstract The introduction of immunotherapies has been paradigm shifting for cancers that were previously a death sentence. However, preclinical/clinical studies on glioblastoma (GBM) have generated mixed outcomes in patients, likely due to its great heterogeneity of immune microenvironment, particularly the myeloid cell populations. Primary patient studies have been limited by a difficulty in performing longitudinal studies, uncontrolled environmental conditions, and genetic variability. There is also, unfortunately, a paucity of mouse models that effectively re-capitulate the immune microenvironment of the human disease. To address these difficulties, we have established the Qk/p53/Pten (QPP) triple knockout mouse model established in our lab. The QPP model uses a cre-lox system to induce Qk deletion on a Pten−/−; p53−/− background which helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2;QkiL/L PtenL/L p53L/L mice, which develops glioblastoma with survival of ~105 days. We have preliminarily assessed the QPP tumors as a faithful model to study the immune response to GBM and found them to recapitulate human GBM with respect to differential response to checkpoint blockade therapy and myeloid and T-cells histopathologically, particularly regarding upregulation of Arginase-1 (Arg1). Arg1 is the canonical marker for tumor-associated macrophages (TAMs), which is a major population of myeloid cells that greatly infiltrate in human GBM, sometimes making up more than ~30% of all GBM cells. Given TAMs’ prevalence in the tumor microenvironment and their upregulation of Arg1 in both human GBM and our QPP model, we are testing whether manipulation of Arg1 will impact TAM function and influence GBM growth. We are also evaluating arginine metabolism in TAMs effect on T cell function in GBM. Lastly, we have developed a genetically engineered mouse model to study the role of Arg1 knockout in a GBM context in-vivo. Our studies suggest that Arg1 plays an important role in GBM immune interaction.

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Immunotherapy of Mouse Leukemia with Monoclonal Antibodies Directed against Type-C Virus Structural Proteins

Tumori Journal ◽

10.1177/030089168407000102 ◽

1984 ◽

Vol 70 (1) ◽

pp. 9-16

Author(s):

Mauro Boiocchi ◽

Piera Mondellini

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Cell Surface ◽

Therapeutic Effect ◽

Structural Proteins ◽

Leukemia Cells ◽

Envelope Glycoproteins ◽

Mouse Leukemia ◽

Type C

The monoclonal antibody A6, isolated during a study on the natural immunoresponse of BALB/c mice against leukemia cells (4), reacts with the envelope glycoproteins gp70 of the MuLV and with the cell surface of the SL2 AKR leukemia. In the present paper, we describe the in vivo immunotherapeutic effect exerted by the A6 monoclonal antibody on the growth of the transplanted leukemia SL2. The greater therapeutic effect observed when the A6 was used with exogenous complement cooperation suggests that the immunotherapeutic activity is mediated by C'-dependent cytotoxicity.

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P044 Milk derived exosomes has a therapeutic effect on experimental colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.173 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S155-S155

Author(s):

R Golan-Gerstl ◽

N Koroukhov ◽

Y Elbaum Shiff ◽

I Shilo ◽

S Reif

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Therapeutic Effect ◽

Experimental Colitis ◽

Intestinal Epithelial ◽

Mice Model ◽

High Concentration ◽

Fluorescent Signal ◽

Proliferation And Differentiation

Abstract Background Inflammatory bowel disease (IBD) is a complex disorder that results from a dysregulated immune response in the gut. Emerging therapy for IBD treatment is mainly focused on regulation of the immune response. Exosomes are nanovesicle packing different molecules such as miRNAs that transfer their cargo to recipient cells. We and others found that mammalian milk contain high concentration of exosomes (milk-derived exosomes, MDE) carrying beneficial miRNAs such as miRNA-148. Furthermore, MDE are taken up by different cell type such as intestinal epithelial cells, modify target gene expression, promote proliferation and differentiation of colon epithelial cells. The aim of this study is to explore the therapeutic effect of MDE on colitis. Methods We used gavage administration of MDE labelled with DiR dye to track their localisation patterns in vivo. The therapeutic effect of MDE on colitis was study in mice model of SDS induced colitis, colon length, histopathological scoring grade, cytokine expression, stool consistency and miRNA expression were analysed. Results Imaging of mouse that have receive labelled MDE revealed an accumulation of fluorescent signal in the intestine. Moreover, fluorescent signal in the intestine and liver is time dependent. MDE reduced the histopathological scoring grade from 5.83 ± 1.47 to 0.6 ± 0.6, p < 0.05. The length of the colon of MDE-treated animals was 7.9 ± 0.19 in comparison to 6.92 ± 0.3 p < 0.05 of the untreated. The weight loss as a result of the colitis was reverted in MDE-treated mice. Likewise, MDE treatment reduced IL-6, TNF-α and caveolin expression from 3.83 to 0.78, 1.59 to 0.86 and 3.52 to 1.1, respectively. Highly expressed miRNAs (miRNA-320, 375, Let-7a and 6073) were found to be more abundant in colon of MDE treatment mice compared with the untreated. Conclusion This study demonstrated that MDE have a therapeutic effect on colitis in vivo. Proving the effect of MDE on colitis will have implications for the potential of adding MDE as a therapeutic nutrient to be included in the formulas for IBD patients.

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